Non-Hodgkin’s Lymphoma

Between 1973 and 1996, the incidence of non-Hodgkin’s lymphoma (NHL) rose by 81% in the United States, representing one of the largest increases of any cancer. Although some of this increase may be artifactual, resulting from improved diagnostic techniques and access to medical care, or may be directly related to the development of NHL in 20- to 40-year-old men with human immunodeficiency virus (HIV) infection, an unexpected increase in frequency of NHL has been observed throughout the United States.

The incidence of NHL per 100,000 persons has risen from 9.8 in 1972-1974 to 13.6 in 1992-1996. The increases have been relatively higher in whites, males, and the elderly, and rates have risen more rapidly in rural than urban areas. Similar findings have been reported in other developed countries.

Currently, NHL represents approximately 4.0% of all cancer diagnoses (4.3% in males and 3.7% in females). Estimates from the American Cancer Society indicate that in the year 2000, some 56,800 new cases of NHL will be diagnosed in the United States and approximately 25,700 people will die of this disease.

Epidemiology

Gender The overall incidence of lymphoma is slightly higher in men than women. The incidence rate (per 100,000 population) in 1989 was 56% higher in white males (17.8) than white females (11.4).

Age Except for high-grade lymphoblastic and small noncleaved cell lymphomas, which are the most common types of NHL seen in children and young adults, the median age at presentation for all subtypes of NHL is over 50 years. Low-grade lymphomas account for 37% of NHLs in patients between the ages of 35 and 64 years at diagnosis but for only 16% of cases in those below the age of 35 and are extremely rare in children.

Race Incidence varies by race, with whites at higher risk than blacks and Asian-Americans. Most histologies, particularly low-grade small lymphocytic and follicular lymphomas, are more common in whites than blacks. The incidence of mycosis fungoides is highest in black males and lowest in white females.

Geography Certain endemic geographical factors appear to influence the development of NHL in specific areas.

HTLV-1-associated NHL Human T-cell lymphotrophic virus-1 (HTLV-1)–associated T-cell lymphoma/leukemia occurs more frequently in Japan (Kyushu) and the Caribbean.

Burkitt’s lymphoma in Africa The incidence (per 100,000 population) of Burkitt’s NHL in Africa (Nigeria and Tanzania) is 5.7-7.6, as compared with 0.1 in the United States. The clinical features of Burkitt’s lymphoma in Africa differ from those of cases reported to the American Burkitt’s Lymphoma Registry. Etiologic endemic factors include malaria as a source of chronic B-cell antigenic stimulation and Epstein-Barr virus (EBV)-induced immortalization of B-lymphocytes.

Middle East lymphoma or a-chain disease a Heavy-chain disease is a disorder of B-lymphoid cells characterized by diffuse thickening of the small intestine due to a lymphoplasmacytic infiltrate with secretion of incomplete IgA heavy chains. This clinicopathologic entity is rarely encountered in individuals other than those of Mediterranean ethnic origin.

Follicular lymphomas are more common in North America and Europe but are rare in the Caribbean, Africa, China, Japan, and the Middle East.

Peripheral T-cell lymphomas are more common in Europe and China than in North America.

Disease site Malignant lymphomas are a heterogeneous group of neoplasms that usually arise or present in lymphoid tissues, such as lymph nodes, spleen, and bone marrow, but that may arise in almost any tissue. The most frequent sites for extranodal lymphomas, which constitute about 26% of all lymphomas, are the stomach, skin, oral cavity and pharynx, small intestine, and CNS. Although primary CNS lymphoma is rare, there has been a 3-fold increase in incidence, even if patients with HIV infection and other types of immunosuppression are excluded.

Survival The 5-year relative survival rate of patients with NHL increased from 28% between 1950 and 1954 to 49% between 1979 and 1985. These improvements in survival occurred mainly in young adults and children. The potential for cure varies among the different histologic subtypes and is directly related to stage at presentation and response to initial therapy.

Etiology and risk factors

Chromosomal translocations and molecular rearrangements Nonrandom chromosomal and molecular rearrangements play an important role in the pathogenesis of many lymphomas and correlate with histology and immunophenotype . The most commonly associated chromosomal abnormality in NHL is the t(14;18)(q32;q21) translocation, which is found in 85% of follicular lymphomas and 28% of higher-grade NHLs. This translocation results in the juxtaposition of the bcl-2 apoptotic inhibitor “oncogene” at chromosome band 18q21 to the heavy-chain region of the immunoglobulin locus within chromosome band 14q32.

The t(11;14)(q13;q32) translocation results in overexpression of bcl-1 (cyclin D1/PRAD 1), a cell-cycle–control gene on chromosome 11q13, and has a diagnostic, nonrandom association with mantle cell lymphoma.

Chromosomal translocations involving 8q24 lead to c-myc deregulation and are frequently seen in high-grade small noncleaved lymphomas (Burkitt’s and non-Burkitt’s types), including those associated with HIV infection.

Environmental factors also may play a role in the development of NHL.

Occupations Certain workers have a slightly increased risk of developing NHL, including farmers, pesticide applicators, grain (flour) millers, meat workers, wood and forestry workers, chemists, painters, mechanics, machinists, printers, and workers in the petroleum, rubber, plastics, and synthetics industries.

Chemicals that have been linked to the development of NHL include a variety of pesticides and herbicides (2,4-D-organophosphates, chlorophenols), solvents and organic chemicals (benzene, carbon tetrachloride), wood preservatives, dusts (wood, cotton), and some components in hair dye.

Chemotherapy and radiotherapy Patients who receive cancer chemotherapy and/or radiation therapy are also at increased risk of developing NHL.

Viruses Several viruses have been implicated in the pathogenesis of NHL, including EBV, HTLV-1, Kaposi’s sarcoma–associated herpesvirus (KSHV; also known as human herpesvirus 8, or HHV-8), and hepatitis C virus (HCV).

EBV is a DNA virus that has been associated with Burkitt’s lymphoma, particularly in endemic areas of Africa; Hodgkin’s disease; lymphomas in immunocompromised patients (ie, organ transplantation and HIV infection); sinonasal lymphoma (Asia and South America); and sporadically in other B- and T-cell lymphomas. EBV can transform lymphocytes in culture. B-lymphocytes from normal EBV-positive subjects grow as tumors in mice with severe combined immunodeficiency.

HTLV-1 is a human retrovirus that is endemic in certain areas of Japan and the Caribbean. HTLV-1 establishes a latent infection via reverse transcription in activated T-helper cells. A minority (5%) of carriers develop adult T-cell leukemia/lymphoma. An HTLV-1–like deleted provirus has been detected in some patients with mycosis fungoides, although conflicting findings have been reported.

KSHV KSHV-like DNA sequences are frequently detected in body cavity–based lymphomas in patients with HIV infection and in those with multicentric Castleman’s disease.

HCV infection is associated with the development of clonal B-cell expansions and certain subtypes of NHL, particularly in the setting of essential (type II) mixed cryoglobulinemia. HCV may predispose B-cells to malignant transformation by enhancing signal transduction upon binding to the CD81 (TAPA-1) molecule.

Immunodeficiency Patients with congenital and acquired states of immunosuppression are at increased risk for NHL.

Congenital immunodeficiency states that are associated with an increased risk include ataxia-telangiectasia, Wiskott-Aldrich syndrome, common variable hypogammaglobulinemia, X-linked lymphoproliferative syndrome, and severe combined immunodeficiency.

Acquired immunodeficiency states, such as HIV infection, iatrogenic immunosuppression (ie, organ or bone marrow transplant [BMT] recipients, long-term survivors of Hodgkin’s disease), and a variety of collagen vascular and autoimmune diseases (eg, Sjgren’s syndrome, rheumatoid vasculitis and Felty’s syndrome, systemic lupus erythematosus, chronic lymphocytic thyroiditis, and angioimmunoblastic lymphadenopathy) also pose an increased risk of developing NHL.

GI lymphomas An increased incidence of GI lymphomas is seen in patients with celiac (nontropical) sprue and inflammatory bowel disease, particularly Crohn’s disease. Gastric mucosa–associated lymphoid tissue (MALT) lymphoma is seen most frequently, but not exclusively, in association with Helicobacter pylori infection. In contrast to studies performed in European patients, Mexican patients with intestinal lymphomas show a very high frequency of EBV-positivity; this finding is not limited to T-cell NHLs, but rather, includes a significant portion of B-cell NHLs.

Signs and symptoms

Fever, weight loss, and night sweats, referred to as systemic B symptoms, as well as fatigue and weakness, are more common in advanced or aggressive NHL but may be present in all stages and histologic subtypes.

Low-grade lymphomas Painless, slowly progressive peripheral adenopathy is the most common clinical presentation in patients with low-grade lymphomas. Patients sometimes report a history of waxing and waning adenopathy before seeking medical attention. Spontaneous regression of enlarged lymph nodes can occur and can cause a low-grade lymphoma to be confused with an infectious condition.

Primary extranodal involvement and B symptoms are uncommon at presentation; however, both are common in advanced or end-stage disease. Bone marrow is frequently involved, sometimes in association with cytopenias. Splenomegaly is seen in about 40% of patients, but the spleen is rarely the only involved site at presentation.

Intermediate- and high-grade lymphomas The clinical presentation of intermediate- and high-grade lymphomas is more varied. Although the majority of patients present with adenopathy, more than one-third present with extranodal involvement, the most common sites being the GI tract (including Waldeyer’s ring), skin, bone marrow, sinuses, GU tract, thyroid, and CNS. B symptoms are more common, occurring in about 30%-40% of patients.

Lymphoblastic lymphoma often presents with an anterior superior mediastinal mass, superior vena cava syndrome, and leptomeningeal disease with cranial nerve palsies.

US patients with Burkitt’s lymphoma often present with a large abdominal mass and symptoms of bowel obstruction.

Screening and diagnosis

No effective methods are available for screening or identifying populations at high risk for the development of NHL. A definitive diagnosis can be made only by biopsy of pathologic lymph nodes or tumor tissue. A formal review by an expert hematopathologist for additional studies, such as immunophenotyping and genotyping, should be considered.

Initial diagnostic evaluation of patients with lymphoproliferative malignancy should include:

PCR and Southern blot studies Circulating monoclonal lymphoid cells can be detected by polymerase chain reaction (PCR) or Southern blot techniques, but the clinical utility of these studies is not well defined. Several studies have demonstrated the presence of circulating t(14;18)–positive cells in patients with durable remissions of follicular lymphoma, but whether this is a harbinger of relapse remains controversial. The t(14;18) translocation has been found in B-cells from blood of normal individuals, indicating that additional oncogenic events are necessary to establish the neoplastic phenotype.

Pathology

Despite an improvement in immunologic, cytogenetic, and molecular techniques used by hematopathologists for diagnosing and classifying lymphoma, many problems and areas of confusion remain.

Working Formulation

Proposed in 1982 as a modification of the Rappaport classification of NHL, the Working Formulation established a uniform language that is clinically relevant and useful in predicting survival and curability (Table 2). This classification is based on two criteria: (1) morphology (growth pattern in lymph nodes and cytologic features of neoplastic cells) and (2) biological aggressiveness (low, intermediate, and high grade).

The terminology is based primarily on the Lukes-Collins and Kiel (Lennert) systems, which recognize the immunologic origin of NHL. Thus, the nodular (follicular) growth pattern represents lymphomas arising from follicular center cells (B-cells) of normal lymphoid follicles, whereas large cell lymphomas are derived from transformed B- or T-cells. The advantages of this classification system include a good correlation between histologic subtype and clinical course, and the potential for widespread application among different institutions because determination of immune surface markers is not required.

Unfortunately, the Working Formulation does not distinguish between neoplasms of B- and T-cell lineage or recognize other subtypes of lymphoma that are defined by immunophenotypic and genetic techniques and/or characterized by unique clinical and biological features . In addition, the Working Formulation classifies immunoblastic lymphoma, a morphologic variant of diffuse large cell lymphoma, as a high grade NHL, and yet its clinical course and survival do not differ from those of intermediate-grade diffuse large cell lymphoma.

REAL classification A revised European-American classification of lymphoid neoplasms (REAL classification) has been proposed by the International Lymphoma Study Group (ILSG). This approach to lymphoma categorization attempts to define the diseases recognized with currently available morphologic, immunologic, and genetic techniques. This system incorporates new lymphoproliferative disorders that were not recognized by the Working Formulation  and omits the general grading of lymphomas into low-, intermediate-, and high-grade categories.

The list of lymphoid neoplasms recognized by the ILSG includes 12 different types of B-cell neoplasms and 11 types of T-cell malignancies, including precursor B-cell and T-cell acute leukemia. The subtypes of Hodgkin’s disease are also included. The clinical relevance of the REAL classification is under study.

The 13 most frequently occurring clinical entities that are recognized by the REAL classification are diffuse large B-cell lymphoma (31%), follicular lymphoma (22%), small lymphocytic lymphoma (6%), mantle cell lymphoma (6%), peripheral T-cell lymphoma (6%), lymphoma of mucosa associated tissue (MALT) type (5%), primary mediastinal large B-cell lymphoma (2%), anaplastic large (T-/null-cell lymphoma (2%), lymphoblastic lymphoma of T- or B-cell lineage, Burkitt’s-like lymphoma (2%), marginal zone (monocytoid) B-cell lymphoma (< 1%), lymphoplasmacytic lymphoma (1%), and Burkitt’s lymphoma (<1%). When immunotyping is used, the diagnostic accuracy of the REAL classification exceeds 85% for most subtypes, with the exception of Burkitt’s-like and lymphoplasmacytic lymphomas, for which the classification has diagnostic accuracy rates of 53% and 56%, respectively.

World Health Organization (WHO) classification The proposed WHO classification for lymphomas will use the principles of the REAL classification and will define each entity according to morphologic features, immunophenotype, genetic features, postulated normal counterpart, and clinical features. The WHO classification is similar to the REAL classification, with some modifications and reassessments based on more current data.

REAL classification vs Working Formulation Several studies have compared the REAL classification with the Working Formulation. In one study, the presence of a T-cell phenotype was associated with a worse prognosis in 68 out of 560 patients with Working Formulation intermediate-grade, immunoblastic NHL. The poor prognoses of these peripheral T-cell lymphomas were independent of the International Prognostic Index (IPI), suggesting that the immunophenotypic basis of the REAL classification is clinically relevant.

However, in a European study of 670 cases of NHL, only 3.8% of cases had a T-cell phenotype, and a statistically significant survival difference could not be demonstrated. In this analysis, mantle cell lymphoma and marginal zone B-cell lymphoma were seen in 11% and 5% of patients, respectively. These histologic subtypes, which are not recognized by the Working Formulation, were characterized by a shorter median survival, suggesting that the REAL classification may be of value in identifying NHL entities with distinct clinical behaviors and prognoses.

Staging and prognosis

Determining the extent of disease in patients with NHL provides prognostic information and is useful in treatment planning. However, histologic subclassification (Working Formulation) is the primary determinant of survival and potential for cure. Compared to patients with limited disease, those with extensive disease usually require different therapy, and certain extranodal sites of involvement, such as the CNS and testes, require specific treatment modalities.

Ann Arbor system Although initially devised for Hodgkin’s disease, the Ann Arbor system has been routinely applied to NHL . Because Hodgkin’s disease commonly spreads via contiguous lymph node groups, this system is based primarily on the distribution of lymphatic involvement with respect to the diaphragm and the presence of extralymphatic organ involvement. The Ann Arbor system does not reflect the noncontiguous nature of disease spread in NHL, does not discriminate well between stage III and IV intermediate-grade disease, and fails to account for tumor bulk or number of extranodal sites.

Prognostic factors Histology and morphology are the major determinants of treatment outcome and prognosis. Some patients with slow-growing low-grade lymphoma may remain well for many years with minimal or no initial therapy, whereas survival of patients with some types of high-grade lymphoma is measured only in weeks, unless aggressive treatment is initiated promptly. The biological and clinical behavior of these disorders varies among the different histologic subtypes.

A new prognostic factor model was recently devised based on a retrospective study of 987 cases of follicular lymphoma. Multivariate analysis showed that gender, age, number of extranodal sites, LDH, systemic symptoms, and erythrocyte sedimentation rate (ESR) were predictors of overall survival. The IPI was also useful in stratifying the same patients into different prognostic groups. In the group of patients 60 years old, gender, systemic symptoms and ESR correlated with survival (Federico M, Vitolo U, Zinzani P, et al: Proc Am Soc Clin Oncol 18:9a [abstract 30], 1999).

Several clinical pretreatment characteristics have been identified that are associated with improved survival after therapy for aggressive (intermediate- and high-grade) NHL: age at diagnosis; performance status; systemic symptoms; serum lactic dehydrogenase (LDH) level; number of nodal and extranodal sites; tumor bulk; b2-microglobulin level (b2M); and Ann Arbor stage. In general, these clinical characteristics are thought to reflect the following host/tumor characteristics:

The IPI was developed by 16 institutions and cooperative groups in the United States, Europe, and Canada as a prognostic factor model for aggressive NHL treated with doxorubicin-containing regimens. Clinical features that were independently predictive of survival included age ( 60 vs > 60 years), LDH ( 1 vs > 1 times normal), performance status (Eastern Cooperative Oncology Group [ECOG] 0-1 vs 2-4), Ann Arbor stage (I-II vs III-IV), and number of extranodal sites ( 1 vs > 1 site).

This index appears to be a very useful guide for selecting treatment for patients with aggressive diffuse large cell NHL by identifying subsets of patients in whom intensified primary therapy may be warranted. Because younger and older patients have markedly different prognoses and because younger patients are more likely to be considered for more intensive investigational regimens, an age-adjusted model for patients 60 years old has been proposed. In younger patients, stage (III or IV), high LDH, and nonambulatory performance status are independently associated with decreased survival.

The IPI also appears to be useful in predicting outcome in patients with low-grade lymphoma and mantle cell lymphoma.

Treatment-related factors Time to complete remission has been identified as an important treatment-related prognostic factor in aggressive NHL. Patients who require > 5 cycles of standard chemotherapy to achieve remission have a high risk of relapse. Similarly, patients with gallium-avid tumors who have persistent gallium uptake at the midpoint of treatment are less likely to have durable remissions.

Dose intensity and schedule The doses of cyclophosphamide (Cytoxan, Neosar) and doxorubicin administered during the first 12 weeks of therapy have been closely associated with survival in aggressive NHL, suggesting that a minimal dose is required to achieve optimal results in diffuse large cell lymphoma and that certain patients may benefit from dose escalation of the most active agents commonly used to treat aggressive NHL. These concepts are currently being tested in randomized clinical trials.

Immunobiological factors Various immunobiological factors have been suggested as predictors of outcome in NHL.

Immunophenotype Several studies have suggested that patients with aggressive nonanaplastic T-cell NHL have a higher relapse rate and decreased overall survival compared with patients with B-cell disease.

Tumor cell proliferation Studies using the Ki-67 antibody, a marker of nuclear proliferation, have shown that increased tumor cell proliferation is a poor prognostic factor in diffuse large cell lymphoma and diffuse small cell lymphoma.

Antigen expression Because tumor antigens may be recognized in association with major histocompatibility complex (MHC) molecules, it has been postulated that the absence of MHC-encoded recognition structures could limit host tumor immunosurveillance. In a small series of patients with large cell lymphoma, the absence of human leukocyte antigens D-related (HLA-DR) in the tumor was associated with significantly shorter median survival. Similar investigations have correlated decreased HLA antigen expression with deficient numbers of CD8+ tumor-infiltrating lymphocytes (TILs), prompting speculation that loss of tumor MHC molecules results in low TILs.

Adhesion molecule expression Lymphomas expressing lymphocyte-homing receptor (CD44), which facilitates lymphocyte migration, are more likely to disseminate than are CD44-negative lymphomas. Several studies have shown that higher levels of CD44 expression in lymphoma are associated with more advanced stage at presentation and decreased survival.

Cytogenetic abnormalities and oncogene expression Lymphomas with abnormalities involving chromosomes 1, 7, and 17 have a worse prognosis than other lymphomas of similar stage and bulk that do not exhibit these changes. Mutations of p53 are associated with histologic transformation in follicular NHLa phenomenon frequently associated with a poor prognosis.

Treatment

The most important therapeutic modality is chemotherapy , especially for intermediate- and high-grade NHL. Surgery is useful in selected situations, such as GI lymphoma, particularly if the disease is localized or if there is a risk of perforation. Orchiectomy is part of the initial management of testicular lymphoma. Radiation therapy plays a more limited role in the treatment of NHL but is useful in localized disease and for palliation. A careful general evaluation of the patient is necessary to assess any contraindications to the planned treatment.

TREATMENT OF Low-grade lymphomas

As a group, low-grade lymphomas (groups A, B, and C  are characterized by indolent clinical behavior and comparatively prolonged survival (median survival, 6-10 years). Many low-grade lymphomas present in elderly patients, who often have coexistent medical illnesses. Most patients have advanced-stage disease at diagnosis, and only about 10%-20% have stage I or II disease. There is little potential for cure when the disease presents in more advanced stages, and treatment is usually palliative.

The standard management of low-grade NHL is controversial and ranges from the “watch and wait” approach pioneered at Stanford University to the use of combination regimens containing doxorubicin (Adriamycin and others), such as CHOP (cyclophosphamide, doxorubicin HCl, Oncovin, and prednisone) or ProMACE-MOPP (prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, mechlorethamine, Oncovin, and procarbazine). A substantial proportion of patients are asymptomatic at presentation. However, the majority of patients require treatment within a few years because tumor growth produces symptoms, compromises vital organs, creates anxiety, or is cosmetically unacceptable. Whereas a watch and wait approach is appropriate for older patients, newer treatment approaches are being tested in younger patients whose longevity is likely to be reduced by their disease.

Stage I and II disease

Most patients with clinical stage I or II lymphoma have occult widespread disease. In contrast to Hodgkin’s disease, most cases of lymphoma do not spread in a predictable pattern from one nodal region to the next adjacent site. Thus, total nodal irradiation and other wide-field radiation techniques, which have proved so successful in treating stages I and II Hodgkin’s disease, have yielded significantly lower disease-free survival in patients presenting with localized NHL.

Involved-field radiation therapy may be the treatment of choice in localized low-grade NHL of the head and neck; it results in a 5-year survival rate of > 50%. Some orbital lymphomas also demonstrate high disease-free survival rates with radiation therapy alone. Moderate-dose (3,000-3,500 cGy) locoregional radiation therapy resulting in 10-year disease-free survival has been reported in carefully staged patients, suggesting that some of these patients may be cured. Older patients (> 55-60 years old) are candidates for watchful waiting or locoregional radiotherapy approaches.

Adjuvant chemotherapy The issue of whether adjuvant chemotherapy improves the prognosis of patients with early-stage low-grade NHL remains unresolved. It is not unreasonable to offer adjuvant chemotherapy to selected stage II patients with unfavorable prognostic factors, such as systemic symptoms or more than two (or discontiguous) nodal sites, and to those with follicular mixed histology.

Stage III and IV disease

Younger patients The management of younger patients with advanced low-grade lymphoma is probably the most controversial area in the treatment of NHL. Some of these patients will enjoy prolonged survival without initial therapy. Median disease-free survival is almost always between 1.5 and 3 years, and median overall survival ranges from 5 to 7 years. Patients with stage III disease have a better prognosis than patients with stage IV disease. Overall, 75% of patients with stage III disease can be expected to survive 5 years.

Chemotherapeutic options in younger patients with low-grade advanced disease include single-agent chemotherapy (chlorambucil [Leukeran] or cyclophosphamide with or without prednisone), CVP (cyclophosphamide, vincristine, and prednisone), or CHOP. Newer agents, such as fludarabine (Fludara) and cladribine (2-CdA [Leustatin]), have significant antitumor activity in low-grade NHL and merit further study, perhaps in combination regimens.

Interferon The use of interferon-alfa (Intron A, Roferon-A) concomitantly with or as an adjuvant to conventional chemotherapy in follicular lymphoma appears to prolong disease-free survival, but its impact on overall survival and curability is controversial.

Recently, a meta-analysis of randomized trials concluded that IFN-a prolonged overall survival in follicular lymphoma patients receiving more intensive initial therapy with doxorubicin/mitoxantrone (Novantrone)-containing regimens, as compared with patients receiving less intensive initial therapy with single- agent alkylator therapy or CVP. However, the Southwest Oncology Group (SWOG) reported that the use of IFN-a after intensive induction chemotherapy with ProMACE-MOPP did not prolong relapse-free survival or overall survival in patients with advanced follicular NHL.

These conflicting results make it difficult to specify recommendations regarding the role of IFN-a in the management of follicular lymphoma. Moreover, this agent is associated with substantial side effects, as compared with some of the newer agents, such as the monoclonal antibody (MoAb) rituximab (Rituxan; see “Radimmunotherapy” section below).

Antigen-pulsed dendritic cells Investigators at Stanford University have used autologous antigen-pulsed dendritic cells to stimulate host antitumor immunity when infused as a vaccine in patients with previously untreated low-grade follicular lymphoma. All four patients treated in this pilot study developed measurable antitumor cellular responses. Two patients experienced clinical responses (one complete response and one partial response). A molecular response (as measured by PCR analysis) was seen in a third patient.

Patients with poor prognostic factors Unfavorable prognostic factors include extent of bone marrow involvement (> 20%), bulky disease ( 5-7 cm), more than one extranodal site, LDH > 1 times normal values, elevated b2M, and nonambulatory performance status. Patients with these unfavorable clinical features have reduced longevity and are incurable with standard chemotherapy or combined-modality approaches, and should therefore be considered candidates for investigational clinical trials aimed at improving disease-free and overall survival.

Based on data from patients with relapsed disease, cytoreduction to a minimal residual disease state followed by autologous stem-cell transplantation or BMT has been tested as a therapeutic intervention in these patients. Whether this approach improves overall survival or is potentially curative will require longer follow-up and additional testing in randomized clinical trials.

Older patients Because of concomitant medical problems, older patients with asymptomatic, indolent NHL are often observed closely without any initial therapy. The decision to use any of the standard or newer modalities should be individualized, based on the presence of poor prognostic features and the patient’s tolerance of planned therapy. Palliative treatment options include chlorambucil (daily dose, 0.1-0.2 mg/kg) or cyclophosphamide (1.5-2.5 mg/kg) with or without prednisone. Oral pulse chlorambucil (16 mg/m for 5 days at 3-week intervals) usually results in a faster antitumor response compared with daily single-agent alkylator therapy.

TREATMENT OF MALT LYMPHOMAS

Like other low-grade lymphomas, MALT lymphomas are probably incurable with standard chemotherapy approaches. The treatment approach to MALT lymphomas is similar to that used for other low-grade NHLs.

MALT lymphoma affecting the stomach is associated with previous H pylori infection, but a causative role for this organism is unproven. Complete eradication of H pylori after treatment with bismuth and/or omeprazole (Prilosec), amoxicillin, and metronidazole frequently leads to disappearance of symptoms and histologic complete remission. In most cases, some evidence of histologic response to treatment of the H pylori infection is evident 2-3 months following eradication of the organism.

A recent long-term follow-up study of antibiotic treatment in 120 patients with gastric MALT lymphomas reported complete responses in 79%, partial responses in 10%, and no responses in 11%. In patients who did not achieve a complete response, there was a significant chance of finding an aggressive lymphoma at surgery. Among the complete responders, only nine relapses have occurred at a median follow-up of 32 months. This study confirms that antibiotics are very effective in treating gastric MALT lymphomas but patients with no or only partial responses need careful investigation to rule out aggressive NHL.

PCR analyses of individual CDRIII regions using patient-specific primers often demonstrate the persistence of a clonal B-cell population in post-remission samples obtained up to 2 years after successful antibiotic treatment of H pylori infection in patients with gastric MALT lymphoma (Zucca E, Bertoni F, Roggerio E, et al: Proc Am Soc Clin Oncol 18:10a [abstract 31], 1999).

Treatment of Intermediate-grade lymphomas

The treatment of aggressive NHL has evolved from the use of radiotherapy alone in most patients, which is curative in patients with truly localized disease, to the current practice of using combination chemotherapy, which cures up to 90% of patients with stage I disease. High-grade immunoblastic lymphoma is essentially the same as diffuse large cell lymphoma with regard to biological behavior, treatment, and prognosis and thus is included in this section. The most widely used chemotherapy regimen in aggressive NHL is CHOP administered every 3 weeks.

Stage I and II disease

The 5-year relapse-free survival rates with radiation therapy alone are 50%-60% for stage I-IE disease and 10%-40% for stage II-IIE disease. Multi-drug chemotherapy together with involved-field radiation therapy has produced disease-free and overall survival rates significantly superior to those achieved with radiation alone. Combined-modality approaches have yielded 5-year relapse-free survival rates of 78%-95% for stage I-IE disease and 70%-75% for stage II-IIE disease.

Chemoradiation

A nonrandomized study of 142 patients with localized diffuse large cell lymphoma treated with CHOP with or without radiation therapy reported a 99% complete remission rate and an overall relapse-free survival rate of 82% at 5 years. Outcome in the 43% of patients over age 65 years was similar to that in younger patients, in contrast to the inferior results achieved in elderly patients with stage III or IV disease. No statistically significant difference in outcome was observed between patients receiving combined-modality therapy and those given CHOP alone.

A 1995 Eastern Cooperative Oncology Group (ECOG), randomized, phase III trial of 8 cycles of CHOP with or without radiation therapy for early-stage intermediate-grade NHL found that the use of low-dose radiation (3,000 cGy) as consolidation for patients achieving a complete remission after CHOP was significantly better than CHOP alone in terms of 6-year disease-free survival (84% vs 70%). This study excluded stage I patients with favorable features and did not address the issue of how much chemotherapy is necessary when used as a component of combined-modality therapy.

Another cooperative group study conducted by SWOG randomized 401 eligible patients with localized intermediate- or high-grade NHL to receive either CHOP (3 cycles) followed by involved-field irradiation or CHOP (8 cycles) alone. Radiation was given to all sites of initial disease (prior to biopsy or resection). A minimum of 4,000 cGy was delivered with an optional boost of 5,500 cGy for residual overt disease.

Five-year overall survival estimates were 72% for CHOP (8 cycles) and 82% for CHOP (3 cycles) plus radiation. Progression-free survival was also significantly different in the two groups (P = .03). Survival analysis of 127 patients < 60 years old with stage I disease and normal Karnofsky performance score indicated a 97% 4-year survival (4 deaths). This SWOG study concluded that CHOP (3 cycles) plus radiation is more effective and less toxic than CHOP (8 cycles) alone for early-stage nodal diffuse aggressive NHL.

Future studies should focus on symptomatic patients, patients > 60 years old, or those with bulky stage II disease.

Treatment recommendations Since it is unclear how many cycles of CHOP are needed in this setting, it is best to individualize treatment based on the site and bulk of disease, the patient’s ability to tolerate therapy, and the presence of poor prognostic features (older age, high LDH, nonambulatory performance status, high b2M).

Patients with nonbulky (< 10 cm), nodal disease can be treated with 3-4 cycles of CHOP followed by locoregional radiation. Patients with bulky disease (> 10 cm), including large mediastinal masses, probably benefit from 6-8 cycles of CHOP followed by radiation therapy.

Disease site or potential toxicities may influence the treatment plan:

Stage III and IV disease

Early SWOG studies with CHOP reported complete response rates of 50%-55%, with 30%-35% long-term disease-free survival. Single-institution pilot studies of newer regimens, such as m-BACOD (methotrexate, bleomycin, Adriamycin, cyclophosphamide, Oncovin, and dexamethasone; Dana-Farber Cancer Center), ProMACE-CytaBOM (prednisone, methotrexate, Adriamycin, cyclophosphamide, etoposide, cytarabine, and bleomycin; National Cancer Institute [NCI]), and MACOP-B (methotrexate, Adriamycin, cyclophosphamide, Oncovin, bleomycin, and prednisone; Vancouver) resulted in 68%-86% complete response rates with 58%-69% survival rates.

To verify these results, the SWOG conducted a consecutive series of phase II trials with the newer regimens. Complete response rates varied from 49% to 65% and survival rates ranged from 50% to 61%, which were very similar to results obtained with first-generation regimens (ie, CHOP) in a cooperative group setting, emphasizing the need for randomized, comparative trials.

Between 1986 and 1991, 1,138 previously untreated patients with stage II (bulky), III, or IV intermediate- or high-grade NHL were randomized to receive either standard therapy (CHOP) or one of the third-generation regimens (m-BACOD, ProMACE-CytaBOM, or MACOP-B). There was no difference in response rate, time to treatment failure, or overall survival between CHOP and the third-generation regimens. Moreover, the newer regimens were more toxic and expensive. Other randomized comparisons have failed to show an advantage of the third-generation regimens over CHOP.

Treatment recommendations Although CHOP remains the best available standard therapy, it is curative in < 50% of patients, indicating a need for new treatment approaches. The following recommended treatment strategies should be adjusted according to the level of risk, as defined by the prognostic factors validated by the IPI:

Age 60 years at low or intermediate risk Younger patients at low or intermediate risk (ie, normal LDH and ambulatory performance status) have 5-year survival rates > 50%. They should be treated with 6-8 cycles of a standard doxorubicin-containing regimen, such as CHOP.

Age 60 years at high-intermediate or high risk The 5-year survival rate in younger patients deemed at high-intermediate or high risk (high LDH and/or nonambulatory performance status) is < 50%. Since the clinical features that correlate with relapse are also associated with a decreased likelihood of achieving an initial remission, these patients should be offered participation in clinical trials of dose-intensive treatment strategies aimed at improving the rates and durability of complete responses.

Efforts to augment the dose intensity of induction and consolidation therapy include the use of colony-stimulating factors and infusional administration of chemotherapy, as well as conventional and repetitive high-dose therapy with hematopoietic stem-cell support. A City of Hope pilot study of high-dose therapy and autologous stem-cell transplantation as consolidation during first complete or partial remission in poor-risk (IPI high- and high-intermediate-risk group) aggressive NHL was updated recently. The 3-year overall survival was 87% for patients in the high-risk group and 92% for patients in the high-intermediate-risk group. Similarly, updated results of two randomized studies show a benefit of early autologous BMT over standard CHOP or sequential chemotherapy in poor-risk aggressive NHL.

Age > 60 years All patients over the age of 60 years should undergo evaluation of cardiac, pulmonary, and renal function and coexistent illness, which may complicate therapy.

Most older patients with advanced-stage aggressive NHL have 5-year survival rates < 50% as a result of decreased initial response, poor tolerance to therapy, and the need for dose reduction because of age. Approaches to elderly patients should include interventions aimed at preserving or increasing dose intensity and improving tolerance of therapy with the use of cytokines and infusional chemotherapy. Selected physiologically “younger” patients may be eligible for consolidation with high-dose therapy and hematopoietic stem-cell support.

Compromised cardiac or pulmonary function Patients with compromised cardiac function require individualized approaches, such as the use of a regimen that does not contain an anthracycline (eg, CVP [cyclophosphamide, vincristine, and prednisone], C-MOPP [cyclophosphamide, Oncovin, prednisone, and procarbazine], or CEPP [cyclophosphamide, etoposide, procarbazine, and prednisone]); a reduction in total anthracycline dose (eg, by alternating CHOP with C-MOPP or CEPP); or the administration of doxorubicin by continuous infusion. Similarly, bleomycin should not be used in patients with compromised pulmonary function.

tREATMENT OF MANTLE CELL LYMPHOMAS

A recent retrospective multivariate analysis performed in 590 patients with mantle cell lymphoma identified disease stage, extranodal involvement, B-symptoms, LDH, performance status, and age as independent prognostic factors. Thus, the IPI also identified different patient risk groups. In contrast to previous studies, neither cytologic features nor architecture had an impact on survival, although there was a trend toward worse clinical outcome in patients with blastoid histology and diffuse tumor growth pattern. However, a high proliferation index, as determined by Ki-67 staining or number of mitoses per high-power field, was associated with an inferior outcome. The median survival was 3 years, with virtually no long-term survivors, and clinical outcome was not influenced by conventional chemotherapy.

Investigators at M. D. Anderson Cancer Center have used 4 courses of fractionated cyclophosphamide (1,800 mg/m) administered with doxorubicin, vincristine, and dexamethasone (hyper-CVAD) alternating with high-dose Ara-C and methotrexate (A-M) to treat 45 patients with mantle cell lymphoma, including 25 who were previously untreated. Originally designed for the treatment of acute lymphoblastic leukemia, hyper-CVAD/A-M induced a response rate of 94% (complete response, 38%; partial response, 56%) in the mantle cell lymphoma patients. After 4 cycles of this regimen, patients 65 years old were consolidated with either an autologous or allogeneic transplant.

The overall survival and event-free survival rates at 3 years were 92% and 72%, respectively, respectively, in the 25 previously untreated patients (95% confidence interval, 45% to 98%), as compared with 25% and 17%, respectively, in the previously treated patients. Untreated patients had a better 3-year event-free survival rate than a historical control group who received a CHOP-like regimen (72% vs 28%), as well as a superior overall survival rate (92% vs 56%).

Treatment recommendations

Autologous or allogeneic BMT in first complete or partial remission is recommended for patients with advanced-stage disease and poor-risk features as part of a clinical trial. Patients with advanced mantle-cell lymphoma should not receive CHOP chemotherapy alone. More aggressive regimens are recommended, such as the hyper-CVAD/A-M or CHOP in combination with rituximab (Rituxan).

TREATMENT OF High-grade lymphomas

Long-term survival among adults with these rapidly growing lymphomas was uncommon prior to the use of intensive combination chemotherapy and CNS prophylaxis. Although relatively infrequent in adults, high-grade lymphomas constitute the majority of NHLs in children. In general, patients can be divided into good- or poor-risk groups based on the extent of disease, as defined by the presence or absence of bone marrow or CNS involvement, tumor mass 10 cm, and LDH 1.5 times normal. The Ann Arbor staging system is suboptimal but, unfortunately, is still used in this patient population.

Lymphoblastic lymphomas

Lymphoblastic lymphomas were previously included in the diffuse, poorly differentiated category of the Rappaport classification and are sometimes misdiagnosed. These malignancies are histologically and cytologically indistinguishable from the lymphoblasts of acute lymphoblastic leukemia (ALL). Most lymphoblastic lymphomas are of T-cell phenotype.

Patients sometimes exhibit clinical features of both leukemia and lymphoma at presentation or during the course of their disease. Bone marrow involvement is common. Criteria to distinguish between these diseases are arbitrary, such as the presence or absence of > 25% marrow involvement, which is used by some pediatric oncologists. Mediastinal masses are seen in 50%-70% of patients at presentation, sometimes together with the superior vena cava syndrome.

Treatment recommendations Because of the propensity for CNS relapse during the course of lymphoblastic lymphomas, CNS prophylaxis with intrathecal chemotherapy and/or irradiation is part of all successful treatment regimens. Currently, ALL-like regimens utilizing multiple drug combinations in alternating fashion with intrathecal chemotherapy and maintenance therapy for 2-3 years (Table 6) have demonstrated complete response rates of up to 80% with long-term survival rates of 45%.

Specific treatment strategies should be guided by risk factors that are predictive of outcome: standard risk (stage I-III and normal LDH) vs high risk (stage IV; high LDH; bone marrow, CNS, or other extranodal site of involvement). Patients with adverse prognostic features are candidates for consolidation with autologous or allogeneic BMT after the completion of induction therapy.

Small noncleaved cell lymphomas

Small noncleaved cell lymphomas (Burkitt’s and non-Burkitt’s types) are the fastest growing and most aggressive of all the lymphomas. Prolonged staging procedures should be avoided because these neoplasms can double in size in a matter of days. High-risk features include elevated LDH, bone marrow involvement, and unresectable tumor masses > 10 cm.

Treatment recommendations A CHOP-like regimen with mid-cycle high-dose methotrexate for CNS prophylaxis developed at Stanford University  resulted in durable complete remissions in 70%-80% patients without high-risk features but in only 20%-30% of patients with adverse prognostic features. A brief, high-intensity, cyclophosphamide-based regimen devised at Vanderbilt University  achieved durable responses in about 50% of high-risk patients.

Selected patients with high-risk features are candidates for autologous or allogeneic BMT during first complete or partial remission.

CNS prophylaxis

Risk factors for CNS disease include histology (high-grade small noncleaved and lymphoblastic NHL) and special sites of involvement (bone marrow, testis, paranasal sinus, nasopharyngeal, and epidural) by diffuse aggressive NHL. Methotrexate (12-15 mg) or cytarabine (Ara-C; 25 mg/m) can be used for intrathecal therapy.

Stem-cell transplantation in poor-risk aggressive NHL in first remission

Most studies of high-dose therapy and stem-cell transplantation in poor-risk NHL in first complete remission have had encouraging results, particularly in patients with high-intermediate and high-risk diffuse aggressive NHL (as defined by the IPI). These results suggest that further study is warranted.

Single-institution studies have produced excellent overall and event-free survival rates ranging from 60% to 90% in patients with poor-risk features. The predicted results of conventional anthracycline-containing regimens in patients with these features are < 50%. The comparative results of high-dose therapy/stem-cell transplantation vs conventional induction or salvage regimens in slowly or partially responding patients are less straightforward, in part, because of limitations in the design of these studies, which failed to enroll enough patients to make meaningful conclusions.

All of the randomized studies comparing standard therapy vs stem-cell transplantation in first complete or partial remission have been performed in Europe, and similar studies are being conducted in the United States. Participation in these trials is encouraged to help define the optimal timing of stem-cell transplantation in poor-risk NHL.

The lymphoma and transplant committees of SWOG, ECOG, and the Cancer and Leukemia Group B (CALGB) plan to conduct a randomized clinical trial of early vs delayed high-dose therapy for patients with high-intermediate and high-risk diffuse aggressive lymphoma. Patients < 65 years old will receive 5 cycles of CHOP. Patients with chemosensitive disease will then be randomized to receive either 3 more cycles of CHOP or 1 additional cycle of CHOP followed by high-dose therapy and autologous stem-cell transplantation. Patients receiving standard CHOP chemotherapy will be offered transplantation at the time of relapse (see Figure 1). If this trial confirms the benefit of early stem-cell transplantation in poor-risk patients with chemosensitive diffuse aggressive NHL, subsequent studies will focus on increasing the number of patients who become eligible for transplant consolidation (Fisher R: Ann Oncol 10(suppl 3):12 [abstract 35], 1999).

Often, patients with poor-risk NHL in first complete remission are referred to a transplant center after having received their initial therapy elsewhere. It is appropriate to offer such patients high-dose therapy/stem-cell transplantation as consolidation if they initially present with poor-risk features that put them at very high risk of relapse and decreased survival when treated with conventional approaches.

Treatment of cutaneous lymphomas

Mycosis fungoides

The most common lymphoma of the skin, mycosis fungoides, is a cutaneous T-cell NHL. Characterized initially by indolent clinical behavior with limited erythematous patch and plaque lesions, mycosis fungoides gradually progresses to generalized skin involvement, tumor formation, and nodal involvement . Cutaneous T-cell NHLs can be treated with a variety of topical and systemic therapies, but the potential for cure is low except for very early-stage disease.

Early-stage disease Treatments directed at the skin, such as total-skin electron-beam radiation, topical chemotherapy with mechlorethamine or carmustine (BCNU [BiCNU]), and psoralen with ultraviolet A activation (PUVA), are usually used as initial therapy for early-stage disease. Extracorporeal photochemotherapy (photopheresis) is most effective in patients with generalized erythroderma and the Szary syndrome.

Radiation therapy Cutaneous lymphomas are highly sensitive to radiation. Individual symptomatic lesions are well palliated with small electron-beam or orthovoltage radiotherapy fields at doses of 2,000 cGy over 2 weeks. Curative radiation therapy involves total-skin electron-beam irradiation. The six-field technique of Stanford University can treat the entire skin surface to a dose of 3,600 cGy in 9-10 weeks. This very demanding approach requires the patient to stand for approximately an hour per day, 4 days per week. Most responses are of short duration.

Chemotherapy and combined-modality therapy Single-agent and aggressive combination chemotherapy regimens can lead to complete responses in 30%-50% of patients. However, most responses are of short duration. A randomized trial showed no survival advantage of total-skin electron-beam radiation plus combination chemotherapy over a conservative approach consisting of sequential topical therapies.

Thus, state-of-the art therapy is generally considered palliative, and most patients are candidates for clinical trials evaluating new treatment approaches, such as interferons, retinoids, immunoconjugates, and purine analogs. Current studies at the City of Hope National Medical Center include the use of combined photopheresis and interferon and denileukin diftitox (DAB389IL-2 [Ontak]), an immunotoxin directed against the interleukin-2 (IL-2) receptor (see “Immunotoxins”).

Treatment of HIV-related lymphomas

Most lymphomas seen in patients who have HIV infection are of high-grade histology (immunoblastic and small noncleaved cell) and advanced stage at presentation. Extranodal disease is common, with unusual sites of presentation, including the rectum, CNS, and multiple soft-tissue masses. Some patients present with primary CNS lymphoma. Poor-risk factors include high LDH, large tumor bulk, extranodal disease, and low CD4 counts (< 100 cells/L).

Chemotherapy

Because of their increased risk for opportunistic infections and impaired hematologic reserve, many patients are unable to tolerate aggressive chemotherapy regimens. Attenuated-dose regimens (such as CHOP or m-BACOD, with 50% reduction of the doxorubicin and cyclophosphamide doses plus growth factor support) are well tolerated, although hematologic toxicity remains a problem in some patients.

Novel oral or infusional combination chemotherapy regimens designed to produce responses and preserve an optimal quality of life are currently being tested. A subgroup of patients without adverse prognostic factors achieve durable remissions when treated aggressively. CNS prophylaxis with intrathecal chemotherapy is necessary to prevent meningeal dissemination. (For a more detailed discussion of HIV-related NHL.

Targeted therapy of NHL

The biotechnology revolution has led to the development of targeted therapies for NHL, including unconjugated antibodies, radioimmunotherapy, and immunotoxins.

Rituximab

Rituximab (Rituxan) is a genetically engineered, unconjugated, chimeric murine/human monoclonal antibody (MoAb) that targets the CD20 antigen found on the surface of most (> 90%) B-cell lymphomas. The FDA recently approved this product for use as a single agent in the treatment of relapsed low-grade follicular NHL, and it is also under investigation for use in combination regimens for follicular, mantle cell, and diffuse aggressive NHL. When administered weekly for 4-8 weeks, rituximab produces a 48%-57% overall response rate in patients with relapsed low-grade lymphoma.

Dose adjusted EPOCH (etoposide, Oncovin, cyclophosphamide, and doxorubicin HCl) has been used by NCI investigators to treat patients with HIV-associated NHL. The complete response rate was 70%, and 2-year progression-free survival and overall survival rates were 83% and 72%, respectively. The use of antiretroviral therapy was suspended during EPOCH chemotherapy, without causing irreversible HIV progression (Little R, Pearson D, Steinberg S, et al: Proc Am Soc Clin Oncol 18:10a [abstract 33], 1999).

The new NHL standardized response criteria for the determination of complete response were used to reanalyze the results of the rituximab pivotal clinical trial. The new criteria rely on unidimensional measurements (short axis of a node). Both the complete response and overall response rates were significantly higher (45% and 62%, respectively) when the new and less stringent criteria are applied. An update of the rituximab pivotal trial indicates that the median response duration is 11.6 months.

Retreatment with rituximab is efficacious in about 40% of initially responding patients. In a multicenter study involving 60 patients with indolent lymphoma who had previously responded to rituximab, 7 patients achieved a complete response when retreated. Median duration of response had not been achieved at a follow-up of 7.7+ months.

A 48% response rate to rituximab was observed in low-grade lymphoma patients with bulky tumor masses measuring 10 cm. The median duration of response in these patients was 5.9 months.

A study of rituximab therapy in seven patients with diffuse aggressive B-cell lymphoma who relapsed after autologous transplantation was recently reported. Six patients responded (one complete and five partial responses), and all five who were symptomatic had complete or partial resolution of symptoms.

Interestingly, the highest response rate in the pivotal trial of rituximab was seen in the subgroup who had undergone prior autologous transplantation. These data suggest a possible role for rituximab as consolidation or maintenance therapy given after conventional or dose-intensive treatment. In addition, based on the costs of chemotherapy and the management of adverse events, rituximab compares favorably with combination chemotherapy and single-agent fludarabine.

Adequate numbers of peripheral blood stem cells can be mobilized from patients receiving highly active antiretroviral therapy and chemotherapy for HIV-related NHL. Selected patients with HIV-related lymphoma can tolerate the high-dose myeloablative chemotherapy regimen used in autologous stem-cell transplantation without an increase in regimen-related toxicity (Molina A, Krishnan A, Forman S: J AIDS Hum Retrovirol 21:A38 [abstract], 1999).

Radioimmunotherapy

Phase II trials suggest that radioimmunoconjugated MoAbs result in high overall and complete response rates compared with unconjugated antibodies.

Tositumomab (Bexxar) In a multi-institution study, 60 patients, 58% with low-grade lymphoma and 40% with transformed lymphoma, were treated with tositumomab, an iodine-131 (131I)–conjugated anti-B1 antibody. Patients had received two or more prior chemotherapy regimens and not responded to or progressed during the last regimen. The response rate to the radiolabeled antibody treatment was 67%, compared with a 28% response to the prior treatment (P = .0001). The median response durations were 6.5 months after the antibody vs 3.5 months with prior treatment.

The main toxicity of tositumomab was hematologic, with blood count nadirs occurring at week 5-6 and recovery by weeks 8-9. Nonhematologic toxicity consisted of mild to moderate fatigue, fever, and nausea. Three patients developed antimurine antibodies.

These results indicate that tositumomab is an effective agent for the treatment of relapsed low-grade and transformed lymphoma. Trials of myeloablative doses of tositumomab followed by autologous stem-cell support are currently being conducted.

Another trial of the 131I anti-B1 antibody produced a 100% response rate in 21 patients with previously untreated stage III-IV follicular NHL, suggesting a role for this agent earlier in the course of the disease.

Y2B8 is a yttrium 90 [90Y]–conjugated anti-CD20 murine IgG1 k antibody. Y90 is a pure, high-energy b-emitter with a path length of 5-10 mm, which may be advantageous for the treatment of bulky or poorly vascularized tumors. Y2B8 selectively targets CD20-positive B-cell NHL with a favorable therapeutic index.

The dose-limiting feature of this approach is hematologic toxicity. The degree of bone marrow involvement, as determined by lymphoma and baseline platelet counts, appears to be a better predictor of hematologic toxicity than radiation dose, which was escalated from 0.2-0.4 miC/kg in a phase I/II clinical trial of this agent. These results may allow clinical parameters to replace dosimetry for the safe administration of Y2B8. In this phase I/II study, the overall response rate were 82% among patients with recurrent, low-grade lymphoma and 43% in patients with intermediate grade histology.

Theoretical concerns have been raised that an enlarged spleen will act as an “antibody sink,” thus limiting antibody-specific targeting. Yet, four of eight patients with splenomegaly achieved a response to Y2B8, six of whom had complete resolution of splenomegaly. In contrast, 74% of patients without splenomegaly responded.

Current trials of Y2B8 include a randomized study comparing Y2B8 to rituximab; a trial combining Y2B8 with a lower radiation dose for low-grade lymphoma patients with thrombocytopenia; and a study incorporating Y2B8 into a conditioning regimen for autologous transplantation.

A recent analysis of registry data from the National Marrow Donor Program reported the results of matched unrelated donor marrow transplantation in 158 NHL patients. The majority had relapsed or persistent disease following conventional therapy and presumably were not candidates for autologous transplantation. At 2 years, the progression-free survival and overall survival rates for the entire group of patients were 30%. This approach is associated with a 45% actuarial mortality within 100 days after transplant. Improvement in molecular typing techniques, supportive care, and treatment of graft-vs-host disease and better patient selection may ultimately lead to an improved outcome in this setting (Bierman P, Molina A, Nelson G, et al: Proc Am Soc Clin Oncol 18:3a [abstract ], 1999).

Immunotoxins

CD25 (IL-2) is present on T-cell lymphomas and a subset of patients with indolent B-cell lymphomas and Hodgkin’s disease. Several immunotoxins targeting this marker have been developed.

DAB389-IL2 was recently approved by the FDA for the treatment of CD25-positive mycosis fungoides (cutaneous T-cell lymphoma). This agent is a novel recombinant fusion protein composed of the receptor-binding domain of IL-2 plus the diptheria toxin.

DAB389-IL2 produced a complete or partial response in 30% of patients with relapsed cutaneous T-cell lymphoma. Common adverse events included fever, chills, nausea, a flu-like syndrome, and the capillary leak syndrome. The activity of this agent in CD25-positive low-grade lymphoma is under investigation.

Anti-Tac (Fv)-PE38 Responses to a recombinant immunotoxin, anti-Tac (Fv)-PE38 (LMB-2), composed of a single-chain Fv form of the anti-CD25 antibody (anti-Tac) fused to a truncated Pseudomonas exotoxin, have been reported in patients with cutaneous T-cell lymphoma, hairy cell leukemia, and chronic lymphocytic leukemia.

Treatment of relapsed disease

The City of Hope approach to the management of lymphoma is summarized in Figures 2 and 3 , respectively). Commonly used salvage regimens are listed in Table 9 .

Autologous BMT

High-dose therapy with autologous hematopoietic stem-cell transplantation has been widely used for the treatment of NHL. Recently, there has been a trend toward the use of primed peripheral blood stem cells instead of bone marrow for hematopoietic reconstitution. Results of pilot phase II studies indicate that high disease-free survival rates (20%-50%) can be obtained with such therapy. In addition, updated results of the Parma trial (see box,) have, for the first time, demonstrated improved disease-free and overall survival rates with the use of high-dose therapy compared with a conventional salvage regimen.

The Parma trial enrolled 215 younger ( 60 years old) patients with intermediate- or high-grade NHL that had relapsed (except in the bone marrow or CNS) after initial response to a doxorubicin-containing regimen. The 109 patients who responded to 2 cycles of DHAP (dexamethasone, Ara-C, and Platinol) were randomized to receive either 4 more cycles of DHAP or high-dose therapy (BEAC [BCNU, etoposide, Ara-C, and cyclophosphamide]) plus unpurged bone marrow. Patients in both arms who had tumor masses > 5 cm at relapse received involved-field radiation. At a median follow-up of 63 months, disease-free and overall survival rates were significantly higher (46% and 53%, respectively) in the high-dose therapy group than in the DHAP group (12% and 32%, respectively) (Philip Y, Gomez F, Guglielmi C, et al: Proc Am Soc Clin Oncol 17:16a [abstract], 1998).

Treatment complications

Tumor lysis syndrome is a common complication after treatment of high-grade, bulky NHLs (due to their exquisite sensitivity to therapy and high proliferative capacity). The syndrome is characterized by renal failure, hyperkalemia, hyperphosphatemia, and hypocalcemia.

Measures to prevent this complication include: aggressive hydration, allopurinol, alkalinization of the urine, and frequent monitoring of electrolytes, uric acid, and creatinine. Dialysis is sometimes required. (For a more comprehensive discussion of the tumor lysis syndrome.

Follow-up of long-term survivors

Relapse The most important risk to patients with NHL is relapse. Among patients with diffuse aggressive lymphomas, most recurrences are seen within the first 2 years after the completion of therapy, although later relapses may occur. Early detection of recurrent disease is important because these patients may be candidates for potentially curative high-dose therapy and stem-cell transplantation. Patients with advanced low-grade NHL are at a constant risk of relapse, and late recurrence of disease may be seen, sometimes after the patient has been in remission for more than a decade.

Physical examination at 2- to 3-month intervals and follow-up CT scans at 4- to 12-month intervals are recommended.

Secondary malignancies Long-term survivors are at increased risk for second cancers. In a survey of 6,171 NHL patients who survived 2 or more years, nearly 1,000 patients lived 15 or more years after diagnosis. Second cancers were reported in 541 subjects, with significant excesses seen for all solid tumors, acute myelogenous leukemia, melanoma, Hodgkin’s disease, and cancers of the lung, brain, kidney, and bladder. The actuarial risk of developing a second malignancy at 3-20 years after diagnosis of NHL was 21%, compared with a population-expected cumulative risk of 15%.

Treatment complications With the decline in the role of radiation as part of the initial therapy for NHL, the risk of certain radiation-induced complications has been reduced or eliminated in more recently diagnosed patients. Nevertheless, total-body irradiation is often used as a component of myeloablative conditioning regimens. Also, transplant recipients are at increased risk of developing secondary myelodysplasia and acute myeloid leukemia, regardless of whether or not they received a radiation-containing conditioning regimen.

Long-term survivors need continued follow-up for possible treatment-related complications. Some of these toxicities may still be unknown. Careful documentation of late complications will be important in the design of future treatment strategies aimed at preserving or improving response rates and duration of remission while at the same time reducing toxicity.